ORAI1-mediated calcium influx in lactation and in breast cancer

McAndrew, Damara, Grice, Desma M., Peters, Amelia A., Davis, Felicity M., Stewart, Teneale, Rice, Michelle, Smart, Chanel E., Brown, Melissa A., Kenny, Paraic A., Roberts-Thomson, Sarah J. and Monteith, Gregory R. (2011) ORAI1-mediated calcium influx in lactation and in breast cancer. Molecular Cancer Therapeutics, 10 3: 448-460. doi:10.1158/1535-7163.MCT-10-0923

Author McAndrew, Damara
Grice, Desma M.
Peters, Amelia A.
Davis, Felicity M.
Stewart, Teneale
Rice, Michelle
Smart, Chanel E.
Brown, Melissa A.
Kenny, Paraic A.
Roberts-Thomson, Sarah J.
Monteith, Gregory R.
Title ORAI1-mediated calcium influx in lactation and in breast cancer
Journal name Molecular Cancer Therapeutics   Check publisher's open access policy
ISSN 1535-7163
Publication date 2011-03
Sub-type Article (original research)
DOI 10.1158/1535-7163.MCT-10-0923
Volume 10
Issue 3
Start page 448
End page 460
Total pages 13
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Collection year 2012
Language eng
Abstract The entry of calcium into the mammary epithelial cell from the maternal plasma (i.e., calcium influx mechanisms) during lactation is poorly understood. As alterations in calcium channels and pumps are a key feature of some cancers, including breast cancer, understanding these calcium influx pathways may have significance beyond mammary biology. We show that the store-operated calcium influx protein, Orai1, is increased during lactation whereas the Orai1 activator Stim1, but not Stim2, is downregulated. Stim2 siRNA reduced basal calcium levels in a lactation model. Our results suggest that calcium influx is remodeled in mammary epithelial cells during lactation, with calcium influx increased through Orai1, activated by Stim2. Breast cancer cell lines had increased levels of ORAI1. ORAI1 siRNA in breast cancer cells reduced storeoperated calcium entry and remodeled the calcium influx associated with invasive stimuli. Analysis of microarray data from 295 breast cancers showed that the transcriptional breast cancer subtype with the poorest prognosis (basal) was associated with an altered relationship between the ORAI1 regulators STIM1 and STIM2, and that women with breast cancers with STIM1high/STIM2low tumors had a significantly poorer prognosis. Our studies show that during lactation there is a remodeling in the nature of calcium influx and that alteration in the ORAI1 influx pathway may be a feature of some breast cancers, particularly those with the poorest prognosis. Our studies suggest that this pathway may be a novel therapeutic target for breast cancer treatment in these women.
Keyword Mammary epithelial-cells
Gene-expression signature
Opertated CA2+ Entry
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Sun, 27 Mar 2011, 00:04:24 EST